ABSTRACT
NF-κB signaling is active in more than 50% of patients with pancreatic cancer and plays an important role in promoting the progression of pancreatic cancer. Revealing the activation mechanism of NF-κB signaling is important for the treatment of pancreatic cancer. In this study, the regulation of TNFα/NF-κB signaling by VRK2 (vaccinia-related kinase 2) was investigated. The levels of VRK2 protein were examined by immunohistochemistry (IHC). The functions of VRK2 in the progression of pancreatic cancer were examined using CCK8 assay, anchorage-independent assay, EdU assay and tumorigenesis assay. The regulation of VRK2 on the NF-κB signaling was investigated by immunoprecipitation and invitro kinase assay. It was discovered in this study that the expression of VRK2 was upregulated in pancreatic cancer and that the VRK2 expression level was significantly correlated with the pathological characteristics and the survival time of patients. VRK2 promoted the growth, sphere formation and subcutaneous tumorigenesis of pancreatic carcinoma cells as well as the organoid growth derived from the pancreatic cancer mouse model. Investigation of the molecular mechanism indicated that VRK2 interacts with IKKß, phosphorylating its Ser177 and Ser181 residues and thus activating the TNFα/NF-κB signaling pathway. An IKKß inhibitors abolished the promotive effect of VRK2 on the growth of organoids. The findings of this study indicate that VRK2 promotes the progression of pancreatic cancer by activating the TNFα/NF-κB signaling pathway, suggesting that VRK2 is a potential therapeutic target for pancreatic cancer.
Subject(s)
I-kappa B Kinase , Pancreatic Neoplasms , Animals , Carcinogenesis , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Mice , NF-kappa B/metabolism , Pancreatic Neoplasms/genetics , Phosphorylation , Protein Serine-Threonine Kinases , Signal Transduction/genetics , Tumor Necrosis Factor-alpha/metabolism , Pancreatic NeoplasmsABSTRACT
This study investigated the inhibition mechanism of root growth in wheat seedlings when exposed to different zinc (Zn) concentrations. All applied Zn concentration did not affect seed germination, but reduced root length; in contrast, only Zn at 3mM inhibited significantly the growth of shoot. The loss of cell viability and the significant increases of lignification as well as the increases of hydrogen peroxide (H(2)O(2)), superoxide radical (O(2)(-)) and malondialdehyde levels were observed in the root tissue exposed to Zn treatment. And also, Zn stress led to the inhibition of cell-wall bound peroxidase. Moreover, NADPH oxidase inhibitor diphenylene iodonium could block greatly the elevation of O(2)(-) generation in Zn-treated roots. Therefore, the increased H(2)O(2) generation was dependent on the extracellular O(2)(-) production derived from plasma membrane NADPH oxidase. In addition, the loss of cell viability and the significant increases of lignification in response to the highest Zn concentration may be associated with the remarkable reduction of root growth in wheat seedlings.
